Current antiretroviral treatment regimens represent significant improvements in the management of HIV-1 infection; however, these regimens have not achieved a functional or sterilizing cure. One barrier to achieving a cure may be suboptimal antiretroviral concentrations in sanctuary sites throughout the body, including the central nervous system, gut-associated lymphoid tissue, lymph nodes, and tissue macrophages. This review will focus on the problems associated with achieving effective concentrations in these restricted sanctuary sites, and potential strategies to overcome these barriers.
Sufficient data exist to conclude that antiretroviral drug distribution is not uniform throughout the body. Low tissue/reservoir concentrations may be associated with viral replication. Multiple means to increase drug concentrations in sanctuary sites are being investigated, including modification of currently utilized drugs, blockade of transporters and enzymes that affect drug metabolism and pharmacokinetics, and local drug administration. Accumulating data suggest these methods increase antiretroviral concentrations in reservoirs of viral replication. No method has yet resulted in the complete clearance of HIV.
New strategies for increasing antiretroviral concentrations in predominant sites of viral replication may provide more effective means for elimination of viral sanctuaries. Additional research is necessary to optimize antiretroviral tissue distribution in order to inhibit virus replication fully, and avoid resistance and replenishment of viral reservoirs that may persist in the face of antiretroviral therapy.
aAntiviral Pharmacology Laboratory, University of Nebraska Medical Center
bUniversity of Minnesota
cUniversity of Miami, USA
Correspondence to Courtney V. Fletcher, PharmD, University of Nebraska Medical Center, College of Pharmacy, 986000 Nebraska Medical Center, Omaha, NE 68198, USA. Tel: +1 402 559 4333; e-mail: firstname.lastname@example.org